Insufficient copper (Cu) during perinatal development has a major impact on the central nervous system leading to severe long-term neurochemical and behavioral consequences. The long-range goal of this research is to identify the neurochemical roles of Cu to better understand the elusive mechanisms of Cu-deficient neuropathology. Research in rodents demonstrates that there are selected regional neurochemical alterations induced by Cu deficiency and that restoration of brain Cu following perinatal deficiency may be difficult, if not impossible. Furthermore sensory-motor function is altered in Cu-repleted rats even after months of nutritional supplementation. Human Cu RDAs for pregnancy and lactation may be set too low.
Three specific aims are the focus of this research and will utilize nutritional and genetic models with Holzman rats and mice.
AIM 1 : We will establish the critical dietary Cu level necessary to block expression of permanent behavior alterations and neuropathology. We will determine the biochemical and behavioral outcomes following the imposition of variable dietary copper intakes to rats. Marginal Cu status will also be studied using diet and mice heterozygous for the Cu transporter gene Ctrl +/-.
AIM 2 : We will test two specific hypotheses. Using L-3,4-dihydroxyphenylserine (L-DOPS) to bypass the Cu-dependent enzyme dopamine t3-monooxvqenase we will test if low brain norepinephrine is responsible for altered brain development and motor function. We will determine the role of brain Cu, Zn-superoxide dismutase by comparing the challenge of Cu deficiency in SOD -/- mice to wild-type controls using biochemical and behavioral outcomes.
AIM 3 : We will characterize the genomic, proteomic, and metabolomic profile of Cu-deficient and Cu-repleted brain. Rat brain transcripts will be compared using DNA microarrays. Cerebellar protein profiles will be compared using 2-D gel electrophoresis and mass spectrometry. Brain metabolite profiles will be compared using MS and HPLC technology. ? ?
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